Protein Synthesis Inhibitors II- Tetracyclines, Sulfonamides, Chloramphenicol, UTI agents

Question 1

Tetracyclines

Answer 1

First Generation: TETRACYCLINE

Second Generation: DOXYCYCLINE, MINOCYCLINE

Question 2

Glycylcyclines

Answer 2

Minocycline derivatives

Ex. Tigecycline

Question 3

Tetracyclines/Glycylcyclines Mech of Action

Answer 3

REVERSIBLY binds the 30S ribosomal subunit

Question 4

Tetracyclines/Glycylcyclines- Bactericidal or Bacteriostatic?

Answer 4

Baceteriostatic; bactericidal when present at high concentrations against very susceptible organisms

Question 5

Mechanisms of Resistance against Tetracyclines/Glycylcyclines Abx

Answer 5

Acquisition of genes on mobile elements:

• EFFLUX PUMPS
• RIBOSOMAL PROTECTION PROTEINS
• ENZYMATIC INACTIVATION

Cross-resistance observed between tetracyclines, except for Minocycline
Tigecycline resistant to these mechanisms

Question 6

Tetracyclines Spectrum of Activity

Answer 6

Gram (+) Aerobes:
Staph aureus (primarily MSSA)
others

Gram (-) Aerobes
Anaerobes

Misc.:
LEGIONELLA
CHLAMYDOPHILA
CHLAMYDIA
MYCOPLASMA
UREAPLASMA
RICKETTSIA

Question 7

Tigecycline Spectrum of Activity

Answer 7

Broader spectrum of activity than tetracyclines
Gram (-) Aerobes:
NOT PROTEUS SPP. OR PSEUDOMONAS AERUGINOSA!!

Anaerobes:
BACTEROIDES SPP.

Question 8

Tetracyclines/Glycylcyclines Absorption

Answer 8

Absorption impaired by di- and tri-valent cations (ex. dairy, vitamins)

Question 9

Tetracyclines/Glycylcyclines Distribution

Answer 9

widely distributed
PROSTATE
minimal CSF penetration

Question 10

Tetracyclines/Glycylcyclines Elimination

Answer 10

Kidney- DEMECLOCYCLINE/TETRACYCLINE
Non-renal routes- DOXYCYCLINE, MINOCYCLINE (metab), TIGECYCLINE (biliary)

TETRACYCLINES/TIGECYCLINE ARE MINIMALLY REMOVED DURING HEMODIALYSIS

Question 11

Tetracyclines/Glycylcyclines Clinical Uses

Answer 11

ROCKY MOUNTAIN SPOTTED FEVER
Respiratory infections
STDs
Treatment/prophylaxis of malaria
Polymicrobial infections (Tigecycline)
Acne
SIADH (demeclocycline)

Question 12

Tetracyclines/Glycylcyclines Adverse Effects

Answer 12

PHOTOSENSITIVITY
G.I.- NAUSEA, VOMITING
RENAL- FANCONI-LIKE SYNDROME W/ OUTDATED TETRACYCLINE
PREGNANCY CATEGORY D
Hypersensitivity, particularly of the skin

Question 13

Sulfonamides

Answer 13

1st effective abx used to prevent/treat infections

Led to a dramatic reduction in morbidity/mortality w/ treatable infections

Question 14

Sulfonamides Mech of Action

Answer 14

INHIBITS DIHYDROPTEROATE SYNTHETASE

- inhibits incorporation of PABA into tetrahydropteroic acid

Question 15

Sulfonamides- Bactericidal or Bacteriostatic?

Answer 15

Bacteriostatic

Question 16

Trimethoprim

Answer 16

Developed in the 1950s

Question 17

Trimethoprim Mech of Action

Answer 17

INHIBITS DIHYDROFOLATE REDUCTASE

- interferes w/ conversion of dihydrofolate to tetrahydrofolate

Question 18

Trimethoprim-Sulfamethoxazole (TMP-SMX, Bactrim) - Bactericidal or Bacteriostatic?

Answer 18

BACTERICIDAL in combo w/ synergistic activity

Question 19

Where Timethoprim-Sulfamethoxazole Act

Answer 19

PABA–>DIHYDRO. ACID–>TETRA. ACID–>PURINES

PABA–(Sulfamethoxazole)–X DIHYDROFOLIC ACID

DIHYDROFOLIC ACID–(Trimethoprim)–X TETRAHYDROFOLIC ACID

Question 20

Mechanisms of Resistance Against TMP-SMX

Answer 20

Sulfonamides

• resistance widespread
• PABA overproduction
• Structural Change of Dihydropteroate synthetase
• plasmid mediated production of drug resistand DHPS or decreased bacterial cell wall permeability to sulfonamides

Timethoprim

• chromosomal or plasmid mediated
• plasmid-mediated production of dihydrofolate reductase resistant to trimethoprim
• changes in cell permeability

Question 21

TMP-SMX Spectrum of Activity

Answer 21

Gram (+): STAPH AUREUS, (incl. some MRSA)
Gram (-): STENOTROPHOMONAS MALTOPHILIA
Other: PNEUMOCYSTIS CARINII
Anaerobes: no activity

Question 22

TMP-SMX Absorption

Answer 22

available IV and PO

rapidly and completely absorbed

Question 23

TMP-SMX Distribution

Answer 23

Good distribution, esp. PROSTATE
Penetrates the CSF (TMP more than SMX)
SMX is 70% protein bound

Question 24

TMP-SMX Elimination

Answer 24

Both are eliminated by kidney

DOSE ADJUSTMENTS REQUIRED IN PATIENTS W/ CRCL<30ML/MIN

Question 25

TMP-SMX Clinical Uses

Answer 25

``` ACUTE, CHRONIC, OR RECURRENT UTIs ACUTE OR CHRONIC BACTERIAL PROSTATITIS SKIN INFECTIONS DUE TO CA-MRSA Bacterial Sinusitis Nocardia Pneumocystis carinii pneumonia Stenotrophomonas Toxoplasmosis Listeria monocytogenes ```

Question 26

TMP-SMX Adverse Effects

Answer 26

``` Hematologic: LEUKOPENIA, THROMBOCYTOPENIA, anemias, eosinophilia, agranulocytosis HYPERSENSITIVITY- RASH, Stevens-Johnson, others CRYSTALLURIA G.I. CNS Renal Toxicity Drug-induced Lupus Serum sickness-like syndrome ```

Question 27

TMP-SMX Drug Interaction

Answer 27

Phenytoin- increases phenytoin levels Warfarin- increases anticoagulant effect Methotrexate- decreases renal clearance

Question 28

TMP-SMX Dosing

Answer 28

``` - comes in single and double strength DOUBLE STRENGTH (DS)= 160MG TMP AND 800MG SMX ```

Question 29

Chloramphenicol

Answer 29

Introduced in U.S. in 1949 No longer used here b/c of adverse effects Still used in developing world

Question 30

Chloramphenicol Mech of Action

Answer 30

Binds to 50S subunit of 70S ribosome | Prevents peptide bond formation

Question 31

Chloramphenicol- Bactericidal or Bacteriostatic?

Answer 31

Bacteriostatic except for: H. influenza Strep. pneumo N. meningitidis

Question 32

Mechanisms of Resistance to Chloramphenicol

Answer 32

Reduced permeability or uptake Ribosomal mutation Acetyltransferase inactivation

Question 33

Chloramphenicol Pharmacology

Answer 33

Absorption- well absorbed Distribution- lipid soluble, not highly protein bound, CSF levels 30-50% of serum levels Elimination- metabolized by liver, excreted by kidneys

Question 34

Chloramphenicol Spectrum of Activity

Answer 34

Gram (+)- unreliable against Staph aureus, not active against enterococci Gram (-)- not active against P. aeruginosa Anaerobes- Gram (-) and (+) Rickettsiae sp. spirochetes Chlamydia Mycoplasma

Question 35

Chloramphenicol Clinical Uses

Answer 35

None in U.S. Developing World- pneumonia, bacterial meningitis, typhoid fever Rocky Mountain Spotted Fever

Question 36

Chloramphenicol Adverse Effects

Answer 36

``` Hematologic Gray baby syndrome Optic neuritis anaphylaxis GI intolerance stomatitis porphyria ```

Question 37

Urinary Tract Agents

Answer 37

Nitrofurantoin | Methenamine

Question 38

Urinary Tract Agents Mech of Action

Answer 38

Nitrofurantoin- poorly understood, binds to ribosomal proteins, inhibits stuff Methenamine- Converted in acid pH to ammonia and FORMALDEHYDE, Formaldehyde denatures proteins & nucleic acids

Question 39

Mechanisms of Resistance against Urinary Tract Agents

Answer 39

Nitrofurantoin- poorly understood, rare, chromosomal or plasmid-mediated Methenamine- alkaline urine, no resistance to formaldehyde described